The purpose of this project is to study how the Fc portion of anti-influenza antibodies regulates host immunity during virus infection. The specific activity within the Fc of IgG molecules is determined by both protein sequence and the specific saccharide components within an N-linked, complex, biantennary glycan that exists on all IgG Fes. The titer of neutralizing antibodies present in host serum is the major correlate of protection against influenza virus infection. Historically, neutralizing antibodies have been defined as those that bind the globular head of the viral hemagglutinin (HA), thereby blocking attachment to host cells. More recently, the definition has been expanded to include antibodies that bind the highly conserved stalk domain of the HA and prevent viral entry by blocking fusion with the host cell. We have recently shown that the Fc portion of influenza-specific antibodies can be a critical determinant of the concentration at which antibodies gain neutralizing activity against influenza viruses. The first two aims of this study are designed as a detailed investigation into the role of Fc-FcR engagement in broad-spectrum neutralization of influenza viruses. We will study the role and mechanisms of FcR mediated effector pathways in protection conferred through both anti-HA and anti-neuraminidase (NA) antibodies. The final aim of our study will investigate the role of the Fc glycan in human immunity against influenza viruses. The IgG Fc glycan is a powerful regulator of antibody effector function and its specific saccharide composition can determine whether an antibody has pro- or anti-inflammatory activity in vivo. It has been observed in mice and in humans that exposure to novel immunogens results in various modifications of IgG glycans; however, little is known about how this process is regulated or the biological consequences of such modifications. Our studies, to be conducted with human samples, are designed to address three fundamental questions related to Fc glycosylation as a determinant of immunity against influenza viruses: 1) does influenza virus vaccination induce a change in glycan composition, particularly in sialylation or fucosylation of flu specific IgG Fes in humans, 2) do the route of exposure and age of the patient affect patterns of post-vaccination Fc glycosylation , and 3) how does Fc glycosylation regulate immunity against influenza viruses in in vitro and in vivo models of infection?